These studies are intended to better understand the complex action of nicotine especially as it relates to dependence. The specific aims are to study the degree of tolerance and physical dependence which develops in rats to nicotine, emphasizing dose regimens which parallel the nicotine intake of cigarette smokers. In addition, the in vivo cortical release of noradrenaline associated with these dose regimens will also be determined. Pulsed intravenous injections of nicotine in the dose range of 2.0 - 4.0 Mug/kg will be administered at different rates. Schedules involving continuous infusions and escalating dose-regimens will also be studied. Whenever tolerance develops, we will determine its duration of action. Should physical dependence occur, the abrupt withdrawal syndrome will be characterized. Rebound phenomena will also be studied. Physiological and pharmacological responses will be studied. The effects of nicotine on autonomic nervous system function (blood pressure, pulse rate, electrocardiographic changes, body temperature) and general functional status (motor activity, rotarod coordination, performance) in unanesthetized rats will be monitored. Body weight and fluid intake will also be followed. For each physiological or pharmacological response observed, its time course will be correlated with the time courses for blood-brain 3H-nicotine levels. Comparative studies with the available (+)-isomer are also planned to determine the degree of stereoselectivity involved. These studies are expected to provide basic insights regarding the development of tolerance and physical dependence to nicotine. These phenomena are believed to contribute significantly to the development and maintenance of the smoking habit. Further, these studies may provide useful models to study many clinically relevant effects associated with smoking.